The renin-angiotensin system mediates changes in vascular structure and function in hypertension and probably other pathophysiological conditions. Angiotensin II (Ang II) is known to produce oxidative stress, but little is known about mechanisms that protect the vasculature from Ang II. The overall goal of this project is to define molecular mechanisms that protect blood vessels from oxidative stress and endothelial dysfunction produced by Ang II. Components of the inflammatory response are activated within the vessel wall in many diseases including hypertension. Ang II activates multiple inflammatory mechanisms within vascular cells. Although emerging evidence suggests a major protective role for the anti-inflammatory cytokine interleukin-10 (IL-10) in vascular biology, nothing is known regarding a potential protective role for IL-10 in hypertension. Our first Aim is to use gene targeted mice to examine the role of IL-10 in oxidative stress and vascular dysfunction produced by Ang II. Although oxidative stress appears to play a key role in hypertension, very little is known about the functional importance of superoxide dismutase (SOD) isoforms in hypertension. The manganese isoform of SOD (Mn-SOD) is expressed in relatively high levels in endothelium and is increased in hypertension and inflammation, but the functional importance of this expression is completely unknown. Our second Aim is to use Mn-SOD deficient and transgenic mice to examine the role of Mn-SOD in the vascular oxidative stress produced by Ang II. Recent data suggest that iNOS may be an important mediator of vascular dysfunction. iNOS is expressed in vascular cells in response to inflammatory stimuli and Ang II. In our third Aim, we will use iNOS deficient mice to examine the hypothesis that expression of iNOS contributes to oxidative stress and endothelial dysfunction in response to Ang II. We have obtained preliminary data that support these hypotheses. Our focus on mechanisms of oxidative stress and endothelial dysfunction seems appropriate considering that endothelial dysfunction has a major impact on the vessel wall and has emerged as an independent predictor of clinical events. Studies in this project should provide new insight into mechanisms of vascular protection against Ang II including inflammatory related mechanisms in hypertension. The studies fit well within several major themes of this program - oxidative stress, inflammation, and vascular dysfunction.